Diabetes is a leading cause of morbidity and death in the United States. Obesity is a major risk factor for the[unreadable] most common form of diabetes, type 2 diabetes, which is characterized by resistance to the actions of[unreadable] insulin. We have discovered a novel, secreted protein called resistin that is adipocyte-specific and circulates[unreadable] at elevated levels in obesity. Hyperresistinemia impairs glucose tolerance, and lack of resistin improves[unreadable] hyperglycemia and insulin resistance in mice with diet induced obesity. We hypothesize that 1) resistin will[unreadable] alter insulin action and cardiovascular disease in genetic models of obesity and atherosclerosis; 2) cellular[unreadable] actions of resistin involve induction of SOCS-3 and/or inhibition of AMPK, mediated by discrete biochemical[unreadable] forms of resistin; and 3) that the effects of mouse resistin are translatable to the human. These hypotheses[unreadable] will be directly tested in the experiments proposed in this project. Specific Aim 1 is to determine the[unreadable] effects of resistin deficiency in genetic models of obesity and atherosclerosis. We hypothesize that[unreadable] mice lacking resistin will be protected from obesity-associated diabetes and atherosclerosis, and will test this[unreadable] by crossing resistin knockout mice with leptin-deficient ob/ob mice and LDL-receptor null mice, respectively.[unreadable] Specific Aim 2 is to understand the molecular and cellular determinants of resistin signaling. We will[unreadable] systematically test the importance of resistin dimerization in a variety of cell types, focusing on potential[unreadable] mechanisms by which resistin influences glucose metabolism that were cellular assays in different cell types,[unreadable] focusing on the inhibition of AMPK, as well as the activation of SOCS-3 in several cell types. Specific Aim 3[unreadable] is to derive and characterize humanized mouse models of resistin expression and physiology. One of[unreadable] the major questions about resistin concerns the translation of the insights from mouse models to humans.[unreadable] Mouse resistin is derived exclusively from adipose tissue, whereas macrophages are a major source of[unreadable] resistin in humans. Preliminary data suggest that human and mouse resistin signal similarly in mouse cells.[unreadable] Human resistin will be expressed in transgenic mice from a liver specific-transgene as well as the human[unreadable] promoter which, in humans, expresses resistin primarily in macrophages. These studies will test the[unreadable] hypothesis that human resistin functions in the mouse, and will provide novel in vivo systems to determine[unreadable] whether human resistin is a potential mediator of insulin resistance. Together, the proposed studies will[unreadable] address critical questions about the role of resistin as a link between obesity, insulin resistance, and[unreadable] diabetes, and a potential target for intervention in these devastating diseases. These studies have important[unreadable] implications for our society in which diabetes and obesity are rampant.